Abstract Metabolic syndrome, driven mainly by obesity is a global epidemic that increases the risk of several chronic diseases including type 2 diabetes (T2D). T2D is prevalent in male and female African Americans (AAs) of all ages. Low plasma levels of adiponectin, a protein secreted by adipose tissue are implicated in the development of T2D in obese AAs. Although, initially characterized as a xenobiotic nuclear receptor important for defense against toxic agents, the pregnane X receptor (PXR) appears to be linked to lipid and glucose metabolism contributing to the metabolic syndrome epidemic. We find that the impact of PXR on HFD-induced obesity and hyperglycemia is sex- and species-dependent. However, the specific mechanisms linking PXR to these diseases remain unclear. Thus, our long term goal is to identify ethnic- and sex- specific targets for lipid-associated diseases (such as obesity and T2D) that disproportionately threaten cardiovascular health in AAs, to develop novel prevention and treatment strategies. The objectives of our proposal are: 1) to investigate whether PXR polymorphisms, more common in AAs are associated with known increases in obesity risk and 2) to understand the underlying molecular mechanisms by which the PXR gene and/or its variants regulate lipid, glucose, and sex hormone metabolism, leading to either enhanced obesity or T2D upon HFD feeding. Guided by compelling preliminary data, our central hypothesis is that PXR deficiency results in impaired adiponectin signaling leading to insulin resistance and glucose intolerance with more prominent race and sex differences. We will use human blood and liver tissue samples and 3 genetic models of mice with differential PXR activity (wild type, PXR-knockout, and PXR-humanized mice), along with molecular and cellular studies. Aim 1 investigates the effect of the human PXR gene and its polymorphisms on obesity risk in AAs. Aim 2 determines the genetic and metabolic factors that contribute to resistance to HFD- induced obesity in Pxr-null mice. Aim 3 explores the relationship between obesity-induced diabetes and hypoadiponectinemia in mice with different PXR activity. Our studies are novel in using clinically relevant PXR-humanized (hPXR) mice to characterize function and regulation of PXR. This study is significant in providing valuable insights in similarities and differences in phenotypic expression and signal transduction pathways between the mouse PXR and the human PXR gene in contributing to the development of obesity and T2D in the different genders. Our studies should provide ground-breaking advances into pathways that can be targeted for the treatment of obesity and metabolic syndrome in AAs.